Background: Colorectal carcinomas (CRC) with somatic PIK3CA mutations comprise 10-15% of all CRCs. The aim of this study was to examine the characteristics of PIK3CA-mutated CRC in a large well-characterized prospective population-based cohort to determine how these mutations relate to pathology phenotype, clinical outcome, and to other molecular alterations.Design:PIK3CA mutation testing was carried out on 780 incident CRCs from the Melbourne Collaborative Cohort Study (mean age at diagnosis: 68 years). MGMT status was assessed using both immunohistochemistry and methyLight techniques. Microsatellite instability phenotype, KRAS and BRAF V600E mutation status were derived from previous reports. Comparisons were performed using two-sided chi-square tests. Survival curves were plotted using the Kaplan-Meier method and a multivariate Cox regression analysis was performed to determine hazard ratio (HR).Results:PIK3CA mutation was present in 107/780 (14%) of CRCs, and these showed significant differences in the following features when compared to CRC lacking a PIK3CA mutation:

PIK3CA-mutated CRC n = 107

PIK3CA-wildtype CRC n = 673

P Value

Proximal Colonic Location

58/105 (55%)

222/418 (35%)

<0.001

KRAS Mutation

50/107 (47%)

169/673 (25%)

<0.001

Minor Mucinous Component

43/94 (46%)

142/602 (24%)

<0.001

Altered MGMT expression

35/97 (36%)

125/631 (20%)

0.001

CIMP-High

22/101 (22%)

75/646 (12%)

0.004

There was no significant overlap with BRAF V600E mutation (P=0.52). Patients with PIK3CA-mutated CRC had significantly poorer overall survival than those with PIK3CA wild-type CRC when BRAF-mutated CRC were excluded from the analysis (P=0.015; Log Rank Test; HR=1.51 95% CI 1.08 – 2.12).

Conclusions:PIK3CA-mutated CRCs are more likely to be located in the proximal colon and to demonstrate CIMP-high and KRAS mutations but not BRAF mutation. Among patients with wild-type BRAF CRC, PIK3CA mutation was associated with overall poorer survival.Category: Gastrointestinal